To assess whether administration of surgical antimicrobial prophylaxis (SAP) versus absence of SAP is associated with a decreased risk of surgical site infections (SSI) after low-risk cholecystectomies (LR-CCE). Current guidelines do not recommend routine SAP administration prior to LR-CCE. This cohort study included adult patients who underwent LR-CCE and were documented by the Swissnoso SSI surveillance system between 1/2009-12/2020 at 66 Swiss hospitals. LR-CCE was specified as elective endoscopic surgery, age <70, no active cholecystitis, ASA score <3, operating time <120 minutes without implantation of foreign material. Exposure was defined as the administration of cefuroxime or cefazoline ± metronidazole within 120 minutes prior to incision versus no SAP administration. Our main outcome was occurrence of SSI until day 30. Logistic regression models were used to adjust for institutional, patient, and perioperative variables. Of 44 682 surveilled adult cholecystectomy patients, 12 521 (8 726 women [69.7%]; median [IQR] age, 49.0 [38.1-58.2] years), fulfilled inclusion criteria. SSI was identified in 143 patients (1.1%). SAP was administered in 9 269 patients (74.0%) and was associated with a lower SSI rate (adjusted odds ratio [aOR], 0.50; 95% CI, 0.35-0.70; P < 0.001). The number needed to treat to prevent one SSI episode is 100. The overall LR-CCE SSI rate was 1.1%. SAP was associated with a 50% lower overall SSI rate. Patients undergoing LR-CCE may benefit from routine surgical antimicrobial prophylaxis.